Bronchial hyperreactivity, often acquired in early life following an acute phlogistic insult to the airways (e.g., viral respiratory illness), is typically associated with more severe immediate and long-term sequelae in the child. This observation raises two interrelated hypotheses: (1) that the mechanisms regulating non-specific bronchial reactivity vary maturationally; and (2) that acute airways inflammation alters bronchial reactivity in an age-dependent manner. In testing these hypotheses, studies are directed at meeting the following principal goals: A) To assess the maturation of non-specific bronchial reactivity: In anesthetized/paralyzed rabbits of varying post-natal age, measures of airway reactivity will be determined from pulmonary resistance and dynamic compliance dose-response relationships to systemically-administered and inhaled histamine and methacholine. To account for age-related differences in reactivity we will quantify: 1) the contribution of the vagal parasympathetic reflex action; 2) the opposing histamine H1- and H2- receptor influences on airway function; 3) the beta-adrenergic bronchodilator influence; and 4) maturational changes in lung membrane muscarinic-cholinergic receptor binding (receptor density and binding affinity) using the radioligand 3H-QNB. The binding of 3H-QNB will be determined in both the absence and presence of methacholine in order to assess the relative binding potency of the muscarinic agonist. Maturational differences in binding will be compared and contrasted to in vivo responsiveness to methacholine. B) To evaluate age-related effects of inflammation on bronchial reactivity: Histamine and methacholine reactivity will be compared in age-matched rabbits receiving intra-pulmonary saline or the phlogistic agent C5a des arg. Differences in reactivity will be further assessed in terms of altered vagal parasympathetic action, H1 and H2-receptor influences, and beta-adrenergic receptor action. Subsequent lung sections will be: 1) histologically examined and graded for inflammation and 2) evaluated for altered muscarinic-cholinergic receptor binding. These studies investigating both the maturation of non-specific bronchial reactivity and how the latter may be affected by acute airways inflammation should provide new insights into the overall interrelationships between airway reactivity, inflammation and asthma.